PROJECT SUMMARY The United States is in the midst of an opioid overdose crisis. Increasingly, these deaths are attributable to the use of illicit opioids like heroin and fentanyl. Although FDA-approved pharmacotherapies for Opioid Use Disorder (OUD) are available, the utilization rate for these pharmacotherapies is low and the frequency of OUD diagnosis is increasing, indicating a need for improved treatment options. One strategy for addressing this crisis may include the use of vaccines designed to target illicit opioids (i.e., immunoantagonists). These vaccines are intended to prevent the target opioid (e.g., heroin, fentanyl) from entering the brain, blocking the abuse-related effects of the opioid. This fellowship proposes to evaluate two candidate anti-opioid vaccines using behavioral (i.e., drug self-administration) and neurochemical (i.e., in-vivo microdialysis) procedures. Specifically, Aim 1 will determine the effectiveness of a well characterized anti-heroin vaccine to diminish heroin vs. food choice in male and female rhesus monkeys. Given the phylogenetic similarities between rhesus monkeys and humans, the data collected from Aim 1 would be expected to be highly predictive of the pharmacodynamic and pharmacokinetic consequences of vaccination in man. Aim 2 will evaluate the effectiveness of a relatively novel anti-fentanyl vaccine to diminish fentanyl vs. food choice in male and female rats. If this anti-fentanyl vaccine proves to be effective in the rodent self-administration model, we would rapidly progress its evaluation to the rhesus monkeys of Aim 1. Finally, Aim 3 will use in-vivo microdialysis to evaluate the effectiveness of an anti-fentanyl vaccine to diminish opioid-induced dopamine release in male and female rats, providing for a mechanistic correlate to the behavioral effects observed in Aims 1 and 2. Overall, the proposed research will improve our understanding of the potential utility of immunoantagonists for the treatment of OUD.